Effect of Metabolic Syndrome on Parkinson's Disease: A Systematic Review

Evidence shows that metabolic syndrome (MS) is associated with a greater risk of developing Parkinson's disease (PD) because of the increase in oxidative stress levels along with other factors such as neuroinflammation and mitochondrial dysfunction. However, because some studies have reported that MS is associated with a lower risk of PD, the relationship between MS and PD should be investigated. This study aimed to investigate the effect of MS on PD. Two authors searched five electronic databases, namely, MEDLINE, PubMed, Scopus, PsycINFO, Web of Science, and Science Direct, for relevant articles between September and October 2020. After screening the title and abstract of all articles, 34 articles were selected for full-text review. Finally, 11 articles meeting the eligibility criteria were included in the study. The quality of articles was critically evaluated using the Joanna Briggs Institute. Overall, we evaluated data from 23,586,349 individuals (including healthy individuals, with MS and PD) aged 30 years or more. In cohort studies, the follow-up period varied between 2 and 30 years. MS contributed considerably to the increase in the incidence of PD. In addition, obesity, a component of MS, alone can increase the probability of developing neurodegenerative diseases. However, despite few studies on MS and PD, changes in cognitive function and more rapid progression of PD disease has been documented in patients with MS using methods commonly used in research.


' INTRODUCTION
A quarter of the global population is estimated to be affected by metabolic syndrome (MS) (1). The prevalence of MS increases with age. In the United States of America, the prevalence of MS is 20%-25% in adults and 0.6%-13% in university students (2,3). A study involving 1125 nursing professionals of both sexes (average age: 37.1 years) who worked in primary health care in Brazil reported that the prevalence of MS is 23.7% in women and 29.4% in men (4).
The pathogenesis of MS is triggered some factors such as oxidative stress, which attacks cellular macromolecules such as proteins, lipids, and nucleic acids and promotes cellular dysfunction (5). Evidence shows that MS is associated with a higher risk of developing Parkinson's disease (PD) (6,7) because of the increase in oxidative stress as well as other factors such as neuroinflammation and mitochondrial dysfunction (8). However, because some studies have reported that MS is associated with a lower risk of PD, the relationship between MS and PD should be investigated (9).
Studies have indicated that the incidence of PD increases with age. The number of PD cases in the world is expected to double by 2030 (10). PD is the second most common neurodegenerative disease, with a prevalence of 0.3% in the general population, 1% in individuals aged 460 years, and 3% in individuals aged 480 years (11). PD affects central and peripheral neurons, including nigrostriatal dopaminergic neurons that coordinate motor function (12). However, pathological analyses have revealed that 40%-60% of dopaminergic neurons are lost before the onset of motor symptoms (13). Consequently, PD is clinically diagnosed at advanced stage. This non-symptomatic period may vary from 5 to 420 years and is called the prodromal phase of PD (14).
Thus, it is relevant to investigate the effect of MS on PD and thus, improve the understanding of the consequences of ' RESULTS

Selection of studies
The electronic search of databases yielded 1,053 articles (Medline/PubMed: 278; Scopus: 425; PsycINFO: 81; Web of Science: 214; and Science Direct: 55). After excluding 197 duplicates, the title and abstract of the remaining articles were screened based on inclusion criteria. A total of 34 articles were selected for full text review. Finally, 11 articles meeting the established eligibility criteria were included in the study (Figure 1).
Overall, were evaluated data from 23,586,349 individuals (including healthy individuals with MS and PD) aged 30 years or more. In cohort studies, the follow-up period varied between 2 and 30 years. Individuals of both sexes were evaluated in all studies, except one study (22) in which only women were evaluated for methodological reasons (longer hair length in women). Three used secondary data from a national database, the National Health Insurance Service (NHIS) of South Korea (6,7,15).
The included studies used different criteria and guidelines for the diagnosis of MS, which were as follows: four studies (6,16,20,21), the National Cholesterol Education Program Adult Treatment Panel III; two studies (7,22), the Joint Interim Statement (JIS); one study, the harmonized definition of metabolic syndrome (9); and in 4 studies (15,(17)(18)(19), the guideline used for the diagnosis of MS was not mentioned, but only the criteria used.
Six studies (16)(17)(18)(20)(21)(22) used the same scale (the Unified Parkinson's Disease Rating Scale [UPDRS]) to assess the disease progression of PD in participants. A study (20) evaluating the progression of PD reported high UPDRS scores in individuals with MS, i.e., faster progression of PD. However, a study evaluating the association of MS with the occurrence of falls and PD progression (21) revealed that MS is associated with a reduction in the number of falls.
In the present review, the effects of MS on incidence of PD were investigated. Two studies evaluated the cognitive capacity of individuals (16,17). However, other studies evaluated this variable using common scales such as the Montreal Cognitive Assessment (17,18), the Symbol Digit Modalities Test (SDMT) (17,20), and the Mini-Mental State Examination (16,19,21).
There is little evidence in the literature regarding the effect of MS on the incidence of PD. Four studies included in this review investigated the effect of MS on the incidence of PD (6,7,9,15). Only one study (9) reported that the presence of MS indicated a 50% lower risk of developing PD. In two studies (6,7), this trend increased with the number of MS components. A study evaluating prodromal characteristics (18) did not indicate the increased risk of developing PD in individuals with MS.

Quality evaluation of articles
No study was excluded according to the quality assessment carried out for each study design (Tables 2, 3, and 4).

' DISCUSSION
In this systematic review, we investigated the effect of MS on PD. The main finding of this study is that the incidence of PD is high among individuals with MS, confirming the research hypothesis that MS has promotive effects on PD.
In addition, abdominal obesity, overweight, and obesity increase the risk of developing PD among individuals with MS (6,9,15).
Some studies, including a cohort study, investigated the incidence of PD using secondary data of 314,737 individuals aged 440 years (7). In an average 7.3-year follow-up period, 48% of the volunteers developed PD. The incidence of PD was higher in the group with MS. Similar trend was observed among patients with hypertension of both sexes. Another cohort study evaluated 6,641 individuals aged 30-79 years for a period of 30 years (9). A total of 89 individuals developed PD and overweight patients had a suggestively greater risk of PD pathology; however, presence of MS indicated a 50% lower risk of developing a neurodegenerative disease. However, although the follow-up period was long, the sample size of this study was relatively small and may have interfered with the results in terms of incidence.
In this review, a study evaluating secondary data of 17,163,560 individuals aged 440 years found that abdominal obesity increased the risk of PD (6). Moreover, with an average follow-up of 5.3 years, the study found that patients with MS are more likely to develop PD than those without MS. In addition, the study reported a positive association between PD and the number of components of MS in question.
The components of MS include increased waist circumference, a characteristic of abdominal obesity, and waist circumference can be related to dietary patterns. In this sense, a cohort study highlighted the importance of a healthy diet in association with a lower risk of PD development (23). The study evaluated 3,653 individuals of both the sexes (average age: 81.5 years) who were followed up for an average period of 6.94 years, verified the quality of the diet of the participants using a dietary screening tool, and reported 47 incident cases of PD. However, although the follow-up period was short, the number PD of cases was high. This may be because of the high average age of the participants; hence, studies investigating participants with a lower average age for a longer period if time should be conducted. In addition, the authors indicated some limitations such as the small diversity of races in the study population, lack of evaluation of energy consumption, and few food options in the questionnaire used. However, the same study meta-analyzed four more studies on the topic, including 140,617 individuals, and  A sub additive interaction was found between the serum GGT level and obesity in women.
(Continued)  found that a high-quality diet or a healthy eating pattern was associated with a lower risk of developing PD.
In the search for the present review, no studies were identified associating diet, MS, and PD. However, the relationship between diet and PD can be explained by the findings of a study performed in mice (24); the study found that long-term high-fat diet suppresses receptors activated by peroxisome proliferators, increases inflammation and gliosis, and decreases dopaminergic neurons and dendritic spines in the midbrain black substance. In addition, PD mice showed neurological deficits, high anxiety, and movement disorders. Thus, it appears that the changes induced by a long-term high-fat diet interfered with both the development of morphofunctional changes in the central nervous system to facilitate the onset of PD and the existing disease.
Regarding obesity, another human study found that the availability of dopamine D2 receptors (verified by positron emission tomography) was lower in obese individuals (n=10) than in control individuals (n=10). Individuals with lower D2 values had a higher BMI. Dopamine modulates motivation and reward circuits; hence, the deficiency of this neurotransmitter in obese individuals may consolidate pathological nutrition to compensate for the alteration in the circuit (25).
A cohort study assessed the relationship between the levels of gamma-glutamyltransferase (gGT) and the risk of PD and the possible interaction between gGT and obesity or MS (15). It is already known that obesity, diabetes mellitus, and components of MS are related to the serum activity of gGT (26,27); moreover, gGT may be associated with the risk of PD development through neuroinflammation and oxidative stress, which are possible etiological factors of PD (28).
A study included in this review (15) evaluated secondary data of 6,098,405 individuals of both sexes (age: 440 years) who were followed up for an average of 6.4 years and found sex difference in the association between the serum level of gGT and the risk of PD. In men with higher serum gGT activity, the risk of developing PD was low; on the contrary, in women with higher serum gGT activity, the risk of developing PD was high regardless of age, income, BMI, smoking, alcohol consumption, and exercise level. Thus, obese women are more likely to develop PD. According to the authors, the low incidence of PD among obese men may be because of protective effect of uric acid on the development of PD (29).
In this sense, another study found a higher mean uric acid level in men with PD and MS (20). However, this study aimed to investigate the progression of PD in 1022 individuals of both sexes (individuals with MS: n=396 [mean age: 63.9 years] and individuals without MS: n=626 [mean age: 59.9 years]) using a cross-sectional design. To assess the progression of PD, we used the UPDRS, the official reference scale for assessing PD (30) and the SDMT, a cognitive test to assess the processing speed and attention of participants (31). The group with MS had higher UPDRS scores, indicating faster progression of the disease, than the group without MS; however, no difference was found in the SDMT scores between the groups. The authors suggest that treatment of MS may be a new approach to delay the progression of PD. However, a cross-sectional study evaluating the association of MS with the occurrence of falls in 194 elderly individuals with PD (mean age: 73 years) (21) using the UPDRS found no relationship between any component of MS and the severity of PD or occurrence of falls. We believe that the small sample size affected the findings and cognitive performance because no difference was observed between individuals who reported falls and the control individuals. Similarly, a recent study found that executive dysfunction is an independent risk factor for falls in PD (32).
A cohort study investigated the effect of MS on cognition in 787 individuals with PD (16). All participants were more      than 60 years old and were divided into three groups at the end of the 5-year follow-up according to cognitive function: patients with DP and normal cognitive function (PD-CN), patients with PD and mild cognitive impairment (PD-CCL), and patients with PD and dementia (DPD). The study found that the incidence of PD-CCL and PDD was higher among patients with MS than among those without MS. Moreover, patients who received treatment for MS had a lower risk of PPD. Patients with PD-CCL and those with PPD had higher levels of hypertension, glucose, and triglycerides than those with PD-CN. In addition, high triglyceride levels were associated with executive function, language, memory, and visuospatial function in patients with PPD. Thus, the authors suggested that treating MS can be useful in controlling cognitive impairment in PD, confirming the hypothesis that MS affects PD progression.

' CONCLUSIONS
Systematic review of studies revealed that MS contributes considerably to the increase in the incidence of PD. In addition, obesity alone can increase the probability of developing neurodegenerative diseases. However, despite few studies on the relationship between MS and PD, changes in cognitive function and the most rapid progression of PD has been documented in patients with MS, using methods frequently used in research. Hence, the scientific community should focus on the relationship between MS and PD because its understanding can promote advances in the control and prevention of both MS and PD.
' AUTHOR CONTRIBUTIONS Souza APS, Barros WMA and Silva JML contributed to research conception, data collection, interpretation of results and critical review of the manuscript. Silva MRM, Silva ABJ, Fernandes MSS and Santos MERA contributed to data analysis and interpretation, and manuscript drafting. Silva ML, Carmo TS, Silva RKP and Silva KG contributed to manuscript drafting and critical review. Souza SL and Souza VON reviewed the manuscript.